Editorial (Thematic Issue: Targeting Telomere Maintenance Mechanisms in Cancer Therapy)

Author(s): M. Folini

Journal Name: Current Pharmaceutical Design

Volume 20 , Issue 41 , 2014

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The discovery of new cancer-related targets and the development of innovative therapeutic interventions are mainly based on the identification of genes involved in pathways selectively deregulated in cancer cells. The unlimited replicative potential is one of the principal hallmarks of cancer and it requires the activation of telomere maintenance mechanisms (TMMs). Two TMMs are currently known in human cancer, namely telomerase activity and the alternative lengthening of telomere (ALT) mechanisms. Although both TMM appear to be equivalent in their ability to support immortalization, their contribution to tumor growth and survival, and consequently patients’ prognosis, may differ. In the opening review article of the present hot topic issue of Current Pharmaceutical Design, Reddel R. [1] outlines the opportunities and challenges presented by telomeres and TMMs for the clinical management of cancer. Different methods currently used to assess the presence of individual TMM in clinical tumor specimens and the information collected thus far concerning the diagnostic, prognostic and therapeutic potential of TMM are also deeply discussed. Telomeres are specialized DNA-protein structures located at the end of eukaryotic chromosomes. They are essential for continued cell proliferation. Indeed, telomere attrition, which occurs within each cell division, represents a molecular clock that counts the number of times a cell can divide and determines its entry into senescence [1]. Other than acting as a mitotic clock, telomeres play an important role in the maintenance of genomic integrity. As pointed out by Feijoo P. et al. [2], telomere erosion, in a context of impaired cell cycle checkpoint, may constitute an important mutator mechanism during tumoriogenesis. Telomere-driven chromosome instability and the consequent fusion-bridgebreakage cycles represent a mechanism that drives the formation of the unbalanced chromosome rearrangements responsible for the changes in gene dosage as well as the aberrations in the karyotype (e.g., aneuploid, polyploid) that are relevant events on the way toward cancer development [2]. Saretzki G. reports on accumulating evidence showing that telomerase is interconnected with different pathways involved in cell proliferation, thus favoring tumor cell survival independently of its activity at telomere ends (i.e., extra-telomeric functions). These telomere-independent activities of telomerase influence essential cellular processes, such as gene expression, signaling pathways, mitochondrial function as well as cell survival and stress resistance. Understanding these different mechanisms and their complexity in cancer cells might help to design more effective cancer therapies in the future [3]. At present, scanty information is available regarding the molecular underpinnings leading to the establishment of a specific TMM in tumors, but there are indications that a complex network of regulatory factors might be involved. Owing to their documented role in cancer development and progression, it has been reported that the deregulated expression levels of specific microRNAs (i.e., small non-coding RNAs that negatively regulate gene expression) may likely contribute to the activation of a TMM rather than the other during tumorigenesis or to play a role in any aspect of telomere biology. In this context, Santambrogio F. et al. [4] report on available data concerning microRNAs that have been shown to impair telomerase activity or to affect telomere functions in cancer cells. Such a research field is still in its infancy but available data indicate that microRNA-based approaches are promising tools for anticancer therapeutic interventions. Consequently, the possibility to identify microRNAs specifically associated to a TMM may provide useful and innovative therapeutic tools or targets to interfere with the unlimited replicative potential of tumor cells [4]. Since telomerase is ubiquitously expressed in a wide range of human tumors, it has been considered as a good target for anti-cancer therapies. Crees Z. et al. [5], Romaniuk A. et al. [6] and Uziel O. and Lahav M. [7] describe the approaches developed during the last decades to inhibit telomerase, including strategies aimed to interfere with the enzyme’s catalytic activity, the expression of its core subunits and the signalling pathways responsible for the transcriptional regulation and post-transcriptional/translational modifications of the enzyme components. Overall, accumulating evidence from preclinical studies on the effects of telomerase inhibition in human cancer has provided persuasive arguments to indicate that the enzyme is a well-validated cancer target and an ideal tumor-associated antigen [5-7]. Specifically, the interference with telomerase activity or the expression of its components results in the decline of tumor growth as a consequence of progressive telomere erosion, telomere uncapping and/or impairment of the extra-telomeric and pro-survival functions of the enzyme. In contrast, although ALT phenotype is thought to be driven by a recombination–based mechanism, factors that can act as the main engine of this pathway have not yet been fully enumerated. Consequently, inhibitors that could specifically target such a TMM in cancer have not been reported thus far. Whether or not anti-telomerase therapies may be hampered by the emergence of possible adaptive responses is still a matter of debate. It is plausible to hypothesize that prolonged treatment with telomerase inhibitors may exert a selective pressure for the emergence of cells that could become resistant to treatment by activating ALT mechanisms. This notion, together with the evidence that ALT is activated in a significant fraction of solid tumors and that both TMM may coexist within the same tumor, suggests that ALT may exert an unprecedented role in tumor biology and may impinge on the clinical efficacy of telomerase inhibitors and on patients’ outcome [1]. As highlighted by Draskovic I. and Londoño-Vallejo A. [8], the development of ALT-specific therapeutic interventions is of pivotal importance and a better understanding of the molecular details responsible for the ALT-associated recombination activity is urgently warrented. In this context, strategies aimed at preventing telomere recruitment to APBs (the platform where the ALT-associated recombination events seem to occur), strand invasion and annealing (the first molecular events in the recombination process), DNA synthesis and the final template/substrate resolution of the ALTmediated telomere elongation reaction have been suggested to be useful for the identification of potential targets specifically relevant to ALT [8]. Other than interfering with telomerase activity/expression, additional therapeutic opportunities at telomeric level have been envisaged, such as the targeting of telomere-associated proteins (e.g., tankyrase) or the stabilization of telomeric G4 structures. As pointed out by Haikarainen T. et al. [9], tankyrase is a poly(ADP)-ribosylase that plays a pivotal role in several cellular processes, including telomere length regulation, glucose metabolism and cell cycle progression, thus emerging as a promising target for different pathological conditions, including cancer. In this context, the development of tankyrase inhibitors has recently received much attention and several small molecules with the characteristics of lead compounds to be used for proof-of-concept studies in cancer and other tankyrase-related disease have been described [9]. Due to their distinctive structural features likely connected with varied cellular functions, non-B DNA conformations, such as G-quadruplexes (G4), represent attractive targets for drug design. Sissi C. and Palumbo M. [10] report that the elucidation of the telomeric G4 structures has led to the rational development of effective G4-stabilizing agents belonging to different chemical classes and including, among others, natural products (e.g., telomestatin, sanguinarine), polycyclic compounds (e.g., perylenes, naphthalene diimides) and porphyrines (e.g. TMPyP4). Due to the inability of telomerase to extend a G4-folded telomeric substrate, G4 stabilizing agents have been primarily considered as indirect telomerase inhibitors [5-7]. However, it has been reported that G4 ligands may trigger telomere uncapping/dysfunctions, resulting in a rapid induction of programmed cell death in a variety of tumors, as a consequence of their interference with the complex architecture of telomeres [5-7]. This evidence clearly suggests that the anticancer effect of G4 ligands may be largely independent of the presence of active telomerase and, consequently, represent attractive therapeutic agents also for ALT-positive tumor cells. Finally, several findings indicated that interference with telomerase expression/function as well as the stabilization of telomeric G4 structures lead to increased sensitivity of tumor cells to conventional anticancer agents and radiation [2,7]. Nevertheless, telomerase-based cancer therapeutics is moving very slowly to the clinical setting. In this context, active immunotherapy (e.g., GV1001, GRNVAC1, Vx-001) and the unique antagonist (i.e., Imetelstat/GRN163L) of human telomerase are the only telomerase-based therapeutic approaches that have thus far entered clinical trials to defeat cancer [5-7]. The purpose of this special issue, thanks to the contribution of eminent experts in the field, is to give an up-to-date view of the present knowledge about the tight link between telomere biology/maintenance and cancer and how such a network could be exploited to identify novel targets for the development of rationally conceived anticancer therapies.

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Article Details

Year: 2014
Published on: 13 October, 2014
Page: [6359 - 6360]
Pages: 2
DOI: 10.2174/1381612820666140630101745

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